title: Heat shock protein 90 (Hsp90) regulates the stability of transforming growth factor beta-activated kinase 1 (TAK1) in interleukin-1beta-induced cell signaling.
abstract: Heat shock protein 90 (Hsp90) is an abundantly and ubiquitously expressed chaperone with majority of client proteins which act as signal molecules. Transforming growth factor beta-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK), and is essential in interleukin-1beta (IL-1beta) triggered signaling pathways. In the present study, we found that Hsp90 plays an important role in regulating IL-1beta signaling by keeping TAK1 stability. The results showed that the specific inhibitor geldanamycin (GA) of Hsp90 dramatically inhibited IL-1beta stimulated TAK1-MAPKs and TAK1-nuclear factor-kappaB (NF-kappaB) activation, resulting in the decrease of cyclooxygenase-2 (COX-2) protein expression. Silencing Hsp90 expression through RNA interference (RNAi) also down-regulated TAK1, as well as attenuated IL-1beta induced phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and p38 MAPKs, and degradation of IkappaBalpha. The same results were obtained in T6RZC stable cells which initiated IL-1beta-induced cell signaling at the level of the oligomerization and ubquitination of TNF receptor-associated factor 6 (TRAF6). We further found that Hsp90 formed a complex with TAK1 via its N-terminal domain and GA destabilized TAK1 and induced TAK1 degradation through proteasome pathway. Taken together our results demonstrate that Hsp90 regulates IL-1beta-induced signaling by interacting with TAK1 and maintaining the stability of TAK1, suggesting that Hsp90 might act as the chaperone of TAK1 in immune and inflammatory responses related with IL-1 signal cascades.
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210046, PR China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Shi
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Shuping
authors.initials: S
authors.lastname: Fang
authors.forename: Junfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Junhong
authors.initials: J
authors.lastname: Liu
authors.forename: Jiayin
authors.initials: J
authors.lastname: Shen
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Yin
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism; D055550:Protein Stability; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016227:Benzoquinones; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D053583:Interleukin-1beta; D048031:JNK Mitogen-Activated Protein Kinases; D047029:Lactams, Macrocyclic; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D048029:TNF Receptor-Associated Factor 6; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C496540:PTGS2 protein, human; C001277:geldanamycin